Case Studies -
Hereditary Colon Cancer

Genetic Discoveries Offer Hope for Prevention

National Institutes of Health, National Center for Human Genome
Research. "The Human Genome Project: From Maps to Medicine."
Bethesda, MD: U.S. Department of Health and Human Services,
1995.

Case 1: Beth M.'s father died of colon cancer, as did her grandmother.
Now two of her brothers, both in their 40s, have been diagnosed with
colon cancer. Beth, age 37, feels a curse is hanging over her family
and is worried about her future and that of her children.

Case 2: Paul C. was 35 when his doctor told him the grim news: He had
advanced colon cancer. As far as he knew, Paul had no family history
of the disease. But after checking, Paul learned that several aunts
and uncles had died of colon cancer at an early age.

Further research revealed that some members of both Beth and Paul's
families carried an altered gene, passed from parent to child, that
predisposes them to a form of inherited colon cancer, known as
hereditary nonpolyposis colorectal cancer (HNPCC). Sometimes
difficult to diagnose, HNPCC is believed to account for one in six of
all colon cancer cases.

Cancers arise from a multistep process, which involves the interplay
of multiple changes, or mutations, in several different genes, in
combination with environmental factors such as diet or lifestyle. In
the most common, noninherited forms of cancer, the genetic changes are
acquired after birth. But individuals who have an hereditary risk for
cancer are born with one altered gene - in other words, they are born
one step into the cancer process. In hereditary nonpolyposis
colorectal cancer, for instance, children who inherit an altered gene
fro either parent face a 70 to 80% chance of developing this disease,
usually at an early age. Women also face a markedly increased risk of
uterine and ovarian cancer.

Though scientists had known for years that an altered gene was to
blame for this hereditary colon cancer, finding it was tricky for they
had few clues as to where, on any of the 23 pairs of chromosomes, the
gene might reside. Finally, in the spring of 1993, using tools
emerging from the Human
Genome Project, an international team tracked the gene to a region
of chromosome 2. Seven months later, two teams zeroed in on the
culprit. Just three months after that, they had identified a second
gene on chromosome 3 also at work in HNPCC. Together, these genes
account for most cases of this inherited cancer.

These discoveries offer a view of how the Human
Genome Project is likely to transform medicine by opening up new
approaches to prevention. The earliest beneficiaries will be those
families facing a very high risk of colon cancer. First, for those
who choose to take it, will come a simple blood test to determine who
in these cancer-prone families does or does not carry the altered
genes. The consequences could be enormous, for as many as 1 in 200,
or 1 million Americans, may carry one or the other of th ese altered
genes.

Individuals found to carry an altered gene would likely be counseled
to adopt a high-fiber, low-fat diet in the hope of preventing cancer.
They would also be advised to start yearly examinations of the colon
at about age 30. Such exams should help physicians detect any benign
polyps, wart-like growths on the colon, early in the disease process,
and then remove them before they turn malignant. For those
individuals who turn out not to carry the altered genes, the
diagnostic test may be a huge relief, removing the fear they have
lived under and sparing them the need for frequent colonoscopies.

Despite the life-saving potential of such diagnostic tests, numerous
issues need to be resolved before they are introduced into general
medical practice. Genetic testing is not so simple as drawing blood
and telling someone the results. For one thing, the best way to test
large numbers of individuals is by no means clear. In deciding
whether or not to be tested, individuals need information not only
about the disorder and its risk, but also about the test and its
limitations. Equally important, genetic testing must be accompanied
by counseling to help people cope with information about their future
risk, whatever the oucome of the test. Those who test positive and
who are trying to decide what course to pursue will need to know how
effective various strategies, such as frequent colonoscopy and polyp
removal, actually are at preventing colon cancer.

Definitive answers are still lacking for these questions. Broader,
societal issues arise as well, such as how to protect the
confidentiality of genetic information and ensure that it is not used
to discriminate against individuals in employment or insurance.

Even before these colon cancer susceptibility genes were discovered,
the Human
Genome Project had begun planning pilot studies to address these
and other questions about testing for cancer risk. It is important
that these questions be answered now, before widespread testing
begins. The identification of genes involved in hereditary colon
cancer is just one in a long string of discoveries that can be
expected as the Human
Genome Project progresses. Careful attention to these social and
ethical issues now will help prepare the public and the medical
profession for the choices that lie ahead.